Ectopic correction of ornithine transcarbamylase deficiency in sparse fur mice.

The sparse fur (spf) mutant mouse is a model for human X-linked ornithine transcarbamylase (OTC) deficiency. Human OTC cDNA placed under transcriptional control of the mouse OTC promoter was microinjected into fertilized oocytes of spf mice. Two founder lines of transgenic mice were phenotypically and biochemically corrected for OTC deficiency by the expression of the human gene at high levels in the small intestine with little or no expression occurring in the liver. The tissue pattern of expression of transgenic mice bearing the chloramphenicol acetyltransferase gene placed under the control of the mouse OTC promoter parallels these results. These experiments demonstrate that human OTC cDNA is selectively expressed in small bowel by a truncated OTC promoter, and such ectopic expression corrects the spf phenotypic and metabolic features of this inborn error. These data suggest that somatic gene therapy of OTC deficiency can be achieved by intestine-targeted gene transfer.